Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:24][CH2:25][CH:26]=[C:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[N:37][C:32]=2[CH2:31][O:30][C:29]2[CH:38]=[CH:39][C:40]([OH:42])=[CH:41][C:28]1=2>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH:26]=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[N:37][C:32]=4[CH2:31][O:30][C:29]4[CH:38]=[CH:39][C:40]([OH:42])=[CH:41][C:28]3=4)[CH2:10][CH:9]2[CH3:14])=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CC1CNCCC1(O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-Chloro-phenyl)-3-methyl-piperidin-4-ol (1.0 g, 4.6 mmol) in DMF (10 mL) with triethylamine (1.75 mL, 12.54 mmol), was added 5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (1.38 g, 4.18 mmol) dropwise for over a period of about 1.5 hours at about 50° C. The reaction was stirred overnight at about 50° C. The reaction was quenched with water, extracted with ethyl acetate, and evaporated in vacuo. The residue was purified by silica gel chromatography (87:10:3 ethyl acetate:methanol:triethylamine) to yield a brown solid of the title compound.
Reaction SMILES: [C:1](O)(=[O:8])[C:2]1C=CC=CC=1.[CH:10]1[CH:11]=[CH:12][C:13]2N(O)N=[N:16][C:14]=2[CH:15]=1.CCN=C=NCCCN(C)C.CN1CCCNCC1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH:16]1[C:14]2[C:13](=[CH:12][CH:11]=[CH:10][CH:15]=2)[CH2:2][C:1]1=[O:8]
Reactant: O=C(O)c1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN1CCCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (E)-3-(5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (541 mg, 1.48 mmol) and HOBt (400 mg, 2.96 mmol) in DMF (2 mL) was added EDCI (565 mg, 2.96 mmol). The reaction was stirred at rt for 10 min and then added 1-methyl homopiperazine (0.734 mL, 5.92 mmol) followed by DIEA (1 mL). The reaction mixture was stirred at rt for 1 h and diluted with H2O (10 mL). The mixture was extracted with EtOAc, dried over Na2SO4 and concentrated. The crude was purified by preparative TLC eluting with 2% methanol in dichloromethane to give (E)-5-chloro-3-(5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one. LCMS (ES): m/z 462 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[CH3:10][O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([SH:19])[CH:14]=1>ClCCl.CO>[NH3:6].[CH3:10][O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][OH:9])[CH:3]=2)[CH:14]=1
Reactant: OCc1cncc(Br)c1
Reactant: COC(=O)c1cccc(S)c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(Sc2cncc(CO)c2)c1
Product: N
Yield: 62.4 %
Yield: 10 %

Procedure:
Dissolve 3-bromo-5-hydroxymethyl-pyridinium chloridei [Kelly, T. R., Howard, H. R., Koe, K., Sarges, R. J. Med. Chem. 1985, 28, 1368-1371] (1.00 g, 4.45 mmol) in saturated aqueous sodium bicarbonate, extract three times with ethyl acetate, dry combined organic phases over sodium sulfate, condense to afford (5-bromo-pyridin-3-yl)-methanol. Employing the procedure of general method 1 using (5-bromo-pyridin-3-yl)-methanol (832 mg) and 3-mercapto-benzoic acid methyl ester (1.50 g, 8.91 mmol). Purify by SCX column, elute with dichloromethane, then 1:1 dichloromethane/methanol then 1:1 dichloromethane/methanol, 10% ammonia, compound elutes in the ammonia, to yield the title compound as a dark brown oil (380 mg, 1.38 mmol): MS (m/z): 276 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1>C(CN)O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:10][CH2:20][CH2:21][OH:22])=[O:22])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Solvent: NCCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g of ethyl 13,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) are dissolved in 10 ml of ethanolamine and stirred at room temperature for 2 h. The mixture is concentrated to dryness in vacuo and the residue is crystallized from isopropanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-hydroxyethyl)acetamide remains as colorless crystals of m.p. 208-211° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][F:21])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][OH:23].C[O-].[Na+]>>[CH3:22][O:23][C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][F:21])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: FCCCOc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COc1nccc(-c2cc3ccc(OCCCF)cc3s2)n1
Yield: 107.1 %

Procedure:
2-(2-Methoxypyrimidine-4-yl)-6-(3-fluoropropoxy)benzothiophene (1-37, 75 mg, 99%) was prepared in the same manner as in Example 34 as a yellow solid using 2-(2-chloropyrimidine-4-yl)-6-(3-fluoropropoxy)benzothiophene (105c, 70 mg, 0.22 mmol) obtained in Preparation Example 21 and a 0.5 M sodium methoxide methanol solution (0.66 mL, 0.33 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[C:9]1([C:2]2[CH:7]=[CH:6][C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2ccc(-c3ccccc3)nc2)cc1
Yield: 72.1 %

Procedure:
2,5-dibromopyridine (10 g, 42 mmol), phenylboronic acid (13.4 g, 110 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (0.7 g, 1.6 mmol), and potassium phosphate (22 g, 105 mmol) were mixed in 200 mL of toluene and 20 mL of water. Nitrogen is bubbled directly into the mixture for 30 minutes. Next, Pd2(dba)3 was added (0.38 g, 0.4 mmol) and the mixture was heated to reflux under nitrogen for 2 h. The mixture was cooled and the organic layer was separated. The organic layers are washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified by column chromatography eluting with 10% ethyl acetate/hexanes. 7 g of desired product was obtained after purification. (91.8% yield)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH2:16][C:17](=[O:21])[N:18]([CH3:20])[CH3:19])=[O:14])=[C:8]([OH:22])[CH:7]=[CH:6]2)#[N:2].[ClH:23].[NH3:24]>CO>[ClH:23].[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH2:16][C:17](=[O:21])[N:18]([CH3:19])[CH3:20])=[O:14])=[C:8]([OH:22])[CH:7]=[CH:6]2)(=[NH:24])[NH2:2]
Reactant: N
Reactant: CN(C)C(=O)COC(=O)c1c(O)ccc2cc(C#N)ccc12
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)COC(=O)c1c(O)ccc2cc(C(=N)N)ccc12

Procedure:
600 Milliliters of anhydrous methanol was added to 29.8 g of 6-cyano-1-dimethylcarbamoylmethoxycarbonyl-2-naphthol, and dry hydrogen chloride gas was passed through the solution under cooling with ice and stirring to saturate the solution with hydrogen chloride gas, followed by further stirring for 24 hours under cooling with water. The reaction mixture was added dropwise to 3.0 liters of anhydrous methanol, followed by stirring for 1 hour under cooling with ice and the precipitate was collected by filtration. This was added to a solution prepared by passing dry ammonia gas through 240 ml of anhydrous methanol under cooling with ice and stirring to saturate the methanol with the gas, followed by stirring for 96 hours under cooling with water. The precipitate was collected by filtration and washed with 150 ml of methanol, 100 ml of water and 100 ml of acetone. To this collected precipitate was added 100 ml of a methanol solution saturated with dry hydrogen chloride gas, followed by stirring for 2 hours under cooling with ice. The precipitate was collected by filtration and washed with a small amount of diisopropyl ether to obtain a crude product. This was dissolved in 1.2 liter of 50% hydrous methanol and 10 g of active carbon was added thereto, followed by stirring for 1 hour at room temperature. Insoluble matter was filtered off and the filtrate was concentrated to 200 ml under reduced pressure. Then, the precipitate was collected by filtration and washed with small amounts of cold methanol and acetone to obtain 18.7 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[N:38]1([C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:22])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: Cc1ccc(S(=O)(=O)NC(CCCCNC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: C1CCNCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(CCCCNC(=O)OCc2ccccc2)C(=O)N2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a cold (0° C.), nitrogen-blanketed mixture of 2-[[(4-methylphenyl]sulfonyl]amino]-6-[[(phenylmethoxy)carbonyl]amino]hexanoic acid (18.00 g, 44.43 mmol), triethylamine (5.80 mL, 41.43 mmol) and piperidine (4.10 mL, 41.43 mmol) in anhydrous dimethylformamide (80 mL) was added dropwise diphenylphosphoryl azide (8.90 mL, 41.43 mmol). The mixture was stirred at about 0° C. for about 1 hour and at ambient temperature for about 2 hours before it was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase was extracted three additional times with ethyl acetate. The combined extracts were then washed with saturated sodium bicarbonate solution, 1N hydrochloric acid and brine prior to drying and solvent concentration. There was isolated in sufficiently pure state 20.90 g (100%) of the title compound of as pale yellow oil; 1H NMR (CDCl3) δ 7.62 (d, J=8.2 Hz, 2H), 7.30-7.22 (m, 5H), 7.19 (d, J=8.1 Hz, 2H), 5.94 (d, J=8.9 Hz, 1H), 5.09-5.07 (m, 1H), 5.03 (s, 2H), 3.90-3.88 (m, 1H), 3.43-3.36 (m, 1H), 3.09-2.91 (m, 5H), 2.32 (s, 3H), 1.4-1.23 (m, 10H), 1.09-0.97 (m, 2H); 13C NMR (CDC13) ppm 168.28, 156.09, 142.87, 136.43, 136.30, 128.98, 127.95, 127.43, 126.96, 65.81, 52.08, 45.70, 42.67, 40.14, 32.58, 28.72, 25.49, 24.65, 23.64, 21.71, 20.93; IR (KBr, cm-1) 3316, 2938, 2860, 1718, 1634, 1526, 1452, 1416, 1340, 1246, 1162, 1092; MS m/z (MH+) calcd 502.2376, obsd 502.2363.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:35][OH:36])[NH:9][C:10](=O)[CH2:11][CH:12](CN2CCCC(C3C=CC=C(C(F)(F)F)C=3)C2)[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[CH3:37][N:38]([CH:40]=O)[CH3:39].[CH3:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>[Cl-].[Na+].O.O.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:11][CH:12]([C:13]([F:14])([F:15])[F:16])[CH2:40][N:38]3[CH2:37][CH2:42][CH2:43][CH:44]([C:45]4[CH:7]=[CH:2][CH:3]=[C:47]([C:13]([F:16])([F:15])[F:14])[CH:46]=4)[CH2:39]3)[O:36][N:35]=2)=[CH:6][CH:7]=1
Reactant: CCCCCC
Reactant: O=C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)NC(=NO)c1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cl
Product: FC(F)(F)c1cccc(C2CCCN(CC(Cc3nc(-c4ccc(Cl)cc4)no3)C(F)(F)F)C2)c1
Temperature: 120 °C
Yield: 41 %

Procedure:
In a 5 mL sealed tube, N-((4-chlorophenyl)(hydroxyimino)methyl)-4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanamide (30 mg, 56.0 μmol) was combined with DMF (2 ml) and heated at 120° C. for 3 hr. The reaction mixture was diluted with 30 ml of brine/water (1:1) and extracted with ether (2×30 ml). The combined organic layer was washed with brine and water, dried with MgSO4, filtered and concentrated in vacuo to give an oil. This crude material was purified by flash chromatography (silica gel, 12 g, 0% to 30% ethyl acetate in hexanes gradient) to afford an oil. This oil was treated with 4NHCl in dioxane and hexane and concentrated to give 14 mg (41%) of 1-{2-[3-(4-chlorophenyl)-[1,2,4]oxadiazol-5-ylmethyl]-3,3,3-trifluoro-propyl}-3-(3-trifluoromethyl-phenyl)-piperidine hydrochloride as a viscous solid. This solid was a 1:1 mixture of diastereomers by LCMS (MS of each peak showed MH+=518).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.N1C(C)=CC=CC=1C.[C:20]([O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])(=[O:22])[CH3:21]>O1CCCC1>[C:20]([O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1)=[O:27])(=[O:22])[CH3:21]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Cc1nc2cc(N)ccc2o1
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CC(=O)Oc1ccccc1C(=O)Nc1ccc2oc(C)nc2c1
Temperature: 3 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
5-Amino-2-methylbenzoxazole (18.6 g, 0.126 mol) and 2,6-lutidine (14.8 g, 0.138 mol) were combined with 125 mL of tetrahydrofuran and the solution was cooled to 3° C. in an ice-bath under nitrogen. 2-Acetoxybenzoyl chloride (25.0 g, 0.126 mol) was added as a solid, portionwise, so as to keep the temperature below 10° C. An additional 150 mL of tetrahydrofuran was added. After addition of all the 2-acetoxybenzoyl chloride, the ice-bath was removed and after stirring for 2 hr the mixture was poured into 300 mL of water and then combined with an additional 300 mL of water. The solid was collected and washed with water and dried. This afforded 33.6 g (86% yield) of product; m.p. 169°-171° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][S:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19](Cl)=[O:20])[CH3:17].C(N(CC)CC)C>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][C:19]([O:18][CH2:16][CH3:17])=[O:20])=[O:14])[CH2:10][S:11][CH3:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)OC(=O)[C@H](CSC)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)-S-methylcysteine (23.5 g, 0.100 mol) in THF (400 mL) was added dropwise ethylchloroformate (9.6 mL, 0.10 mol) and triethylamine (10.1 g, 0.100 mol) slowly at −10° C. The reaction mixture was stirred at −10° C. for 30 minutes, and then the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give ethoxycarbonyl N-(tert-butoxycarbonyl)-S-methylcysteinate which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])=[CH:4][CH:3]=1.[OH:19]O.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]2[CH2:15][C:14]34[O:19][CH:13]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:8]2=[O:16])=[CH:17][CH:18]=1
Reactant: O=C1C(=Cc2ccc(Cl)cc2)Cc2ccccc21
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2ccc(Cl)cc2)CC23OC2C=CC=C13

Procedure:
Ten grams (0.039 mole) of 2-(p-chlorobenzylidene)-1-indanone is converted to the epoxide in 1 liter of MeOH, using 9.6 g (0.085 mole) of 30% H2O2 and 9.6 ml (0.039 mole) of 16% NaOH, as described in Example 1. Since the starting material is poorly soluble in MeOH it is oxidized as a suspension and the product separates during the course of the reaction (5 hours at 35°-38°). The crude yield is 10 g (94%); m.p. 162°-164°. Crystallization (of 9.7 g) from 70 ml of MeCN gives 8.8 g (86%) of nearly colorless solid; m.p. 165°-167°.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5](C(OC)=O)=[CH:4][CH:3]=1.[CH3:12][Mg]Br.[Cl-].[NH4+].C([O:20][CH2:21][CH3:22])(=O)C>O1CCCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:21]([OH:20])([CH3:22])[CH3:12])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
A solution of methyl p-bromobenzoate (3 g, 13.2 mmol) in tetrahydrofuran (14 mL) cooled to −30° C. was treated dropwise with methyl magnesium bromide (1 M in diethyl ether, 105.5 mmol, 105.5 mL). Upon completion of addition, the resulting suspension was allowed to warm to room temperature and was stirred for 5 hours. Saturated aqueous ammonium chloride (100 mL) was added slowly and the mixture was diluted with ethyl acetate (100 mL). The organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, were filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (10:1 hexanes—ethyl acetate) gave 2.2 g (79% yield) of 2-(4-bromo-phenyl)-propan-2-ol. 13C NMR (100 MHz, CDCl3) d 148.4, 131.4, 126.6, 120.8, 72.5, 31.9; MS (AP/Cl) 197.1, 199.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]1[CH3:15])=O)(C)(C)C.[Cl:16][S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([CH3:30])=[CH:23][N:24]=[CH:25]2)(=[O:19])=[O:18]>>[ClH:16].[ClH:16].[CH3:15][C@H:9]1[CH2:10][NH:11][C@H:12]([CH3:14])[CH2:13][N:8]1[S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([CH3:30])=[CH:23][N:24]=[CH:25]2)(=[O:18])=[O:19]
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Product: Cc1cncc2cccc(S(=O)(=O)N3C[C@@H](C)NC[C@@H]3C)c12
Product: Cl
Yield: 82.8 %

Procedure:
Using 0.34 g of trans-1-(tert-butoxycarbonyl)-2,5-dimethylpiperazine and 0.64 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.43 g of the objective compound (white crystals).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:18]([CH3:20])=[O:19])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI.O>CS(C)=O>[CH3:21][O:16][C:15](=[O:17])[CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[S:18]([CH3:20])=[O:19]
Reactant: CS(=O)C(C(=O)O)c1ccc(-c2ccccc2F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: COC(=O)C(c1ccc(-c2ccccc2F)cc1)S(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 11.5 gm (39.3 millimols) of (2'-fluoro-4-biphenylyl)-methyl-sulfinyl-acetic acid in 60 ml of dimethyl sulfoxide, was admixed with 8.2 gm of dry potassium carbonate and 8.4 gm of methyl iodide, and the mixture was stirred at room temperature for 3 hours. Thereafter, water was added, whereupon the reaction product crystallized out and was suction-filtered off, dried and recrystallized from carbon tetrachloride and isopropanol Yield: 3.8 gm (32% of theory); m.p. 79°-80° C
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:3]=3)[S:9][C:10]=2[C:16]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Temperature: 140 °C
Yield: 44 %

Procedure:
A stirred suspension of 200 mg (0.45 mmol) 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide, 0.39 ml (4.46 mmol) morpholine and 291 mg (0.89 mmol) cesium carbonate in 5 ml N-methylpyrrolidone in a thick-walled glass pressure tube fitted with a teflon cap was heated at 140° C. for 24 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (1/1 ethyl acetate/hexane) followed by trituration in ether and hexane afforded 90 mg (44%) N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-morpholin-4-yl-isonicotinamide as an off-white crystalline solid. ES-MS m/e (%): 477 (M+Na+, 13),455 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]3[N:10]([CH2:11][CH2:12][CH2:13]3)[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:29]=[C:30](Cl)[O:31][C:32](Cl)(Cl)Cl.C(O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:14]3[N:10]([C:9]=2[C:30]([O:31][CH2:32][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])[CH2:11][CH2:12][CH2:13]3)=[CH:6][CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Clc1ccc(-c2cn3c(c2-c2ccccc2)CCC3)cc1
Reactant: OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1c(-c2ccc(Cl)cc2)c(-c2ccccc2)c2n1CCC2
Reaction time: 8 h

Procedure:
6-(4-Chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (Example 17 a, 1.5 g, 5.1 mmol), dissolved in THF (10 ml), is treated with triethylamine (0.7 ml, 0.51 g, 5 mmol). A solution of diphosgene (0.5 g, 2.5 mmol), dissolved in THF (5 ml), is added dropwise to this solution at RT, and it is stirred for 8 h. Benzyl alcohol (abs., 0.52 ml, 0.54 g) and triethylamine (0.7 ml, 0.51 g, 5 mmol) are then added, and the mixture is stirred at RT for a further 48 h. The reaction mixture is partitioned between water (30 ml) and diethyl ether (60 ml), and the ether phase is washed with NaOH (5%, 20 ml). An oily residue is obtained from the THF/ether phase dried using Na2SO4 sicc. after the removal of the solvent in vacuo.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].C1C[O:13][CH2:12][CH2:11]1>>[CH2:2]1[CH:12]([OH:13])[CH2:11][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:1]1
Reactant: C1CCOC1
Reactant: CC(=O)c1ccccc1
Product: OC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
In situ Preparation of the Compound of Formula (II) wherein R1 is ##STR11## Borane methylsulfide complex (neat, ~10M, 1.4 mL, 14 mmol) was added to a solution of cis, exo-3-amino-2-hydroxybornane [J. Chem. Soc. 49, 1970] (169 mg, 1 mmol) in THF (70 mL) at ambient temperature and was stirred for 16 hours. Acetophenone (2.36 g, 24.6 mmol) as a solution in THF (10 mL) was added to the preceding solution over one hour, stirred for fifteen minutes after addition was completed, cooled to 0° C., and quenched with methanol (27 mL). After stirring the quenched reaction for 18 hours, the solvents were removed under vacuum, the residual oil was dissolved in methylene chloride (50 mL), washed with pH 4 phosphate buffer (50 mL), water (50 mL), treated with magnesium sulfate, and the solvent was removed under vacuum to give the (R) phenethyl alcohol. 2.17 g (92% yield) 88% ee.